We have described several members of an Italian family who have markedly reduced plasma high density lipoprotein (HDL) levels (25% of normal) without exhibiting any of the characteristic clinical features of other HDL-deficient disorders, including no evidence of accelerated coronary artery disease. Associated with this new HDL disorder is the presence of a variant form of apolipoprotein A-I which, unlike the normal A-I apoprotein, contains the amino acid cysteine. Our research plan is intended to distinguish the various possibilities for the occurrence of the variant A-I in this family. We have preliminary evidence to support the hypothesis that this variant A-I is in fact a normal component in many individuals rather than an isolated case of mutation and, therefore, that A-I exists as a polymorphic protein (at the level of amino acid sequence) requiring more than one gene for expression. We have extended the observation of A-I variants to the dog. To prove the hypothesis that A-I variants are a general phenonenon, we need to identify and isolate the variant form from other individuals. In addition, to gain insight into the structural relationship between the variant A-I and normal A-I, it will be necessary to carry out amino acid sequence studies on the variant A-I. If our hypothesis proves correct it will provide new impetus for the study of the metabolism of HDL. In the long term we need to understand how the Italian family members have compensated for the lack of normal A-I and, even with very low levels of plasma HDL having an abnormal A-I, why they suffer no apparent clinical manifestations. This is an important question in light of the fact that HDL levels are inversely correlated with coronary artery disease. It will be important to understand the metabolism of the variant-containing HDL subclasses which, in the Italian family are capable of carrying out normal HDL functions.